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Targeting Carbohydrate–Protein Interactions
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Targeting Carbohydrate–Protein Interactions

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 56024

Special Issue Editor

Prof. Dr. László Somsák

E-Mail Website
Guest Editor
Department of Organic Chemistry, University of Debrecen, P.O. Box 400, H-4002 Debrecen, Hungary
Interests: organic synthesis; carbohydrates; c-glycosyl derivatives; anomeric spirocycles; lectine antagonists; glycoenzyme inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Carbohydrates, Nature’s ubiquitous molecules, participate in a plethora of biological phenomena. Besides being well-known constituents of skeletal and storage materials as well as nucleic acids throughout the living world, sugars, in the form of either mono-, oligo-, or polysaccharides, mediate and regulate intrinsic (intraspecies) and extrinsic (interspecies) recognition events, have structural and modulatory roles, and are the subject of molecular mimicry of host glycans (Varki, Glycobiology, 2017, 27, 3–49). Thus, glycosylation appears to be one of the most widespread biochemical modifications of biomolecules, is present in all living cells, and, among other things, is responsible for the enormous diversity of living beings, which can hardly be explained solely based on the genome.

Most of the above phenomena occur via interactions of the respective carbohydrate molecules with specific proteins called lectins. On the other hand, construction of the sugar derivatives and their biologically active conjugates is catalyzed by glycoenzymes, proteins that not only recognize sugars but also transform or attach (or even detach) them to (or from) other chemical entities. The investigation of the molecular basis of these biological events—despite the significant advances that have been made—is at its beginning and, given the huge number of carbohydrate–protein interactions to be studied, may provide further exciting results to be utilized in biomedical fields and possibly translated to therapies.

Indeed, such efforts have already led to marketed drugs, e.g., glycosidase as well as sodium dependent glucose transporter 2 (SGLT2) inhibitors against diabetes, neuraminidase inhibitors to treat influenza, and modified oligosaccharides to be used as anticoagulants. Other molecules are in various phases of clinical investigation, such as a selectin inhibitor against sickle cell disease and galectin inhibitors against fibrogenetic disorders and cancer.

This Special Issue is devoted to studies on the characterization and modulation of carbohydrate–protein interactions focussed on lectins and glycoenzymes. Contributions on any aspect of these fields are welcome, e.g., structural studies, the design and synthesis of small-molecule and multivalent inhibitors, structure–activity relationships, computational approaches, and applications of recognized interactions.

Prof. Dr. László Somsák
Guest Editors

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Keywords

  • lectin
  • glycoenzyme
  • sugar transporter
  • substrate
  • inhibitor
  • multivalency
  • synthesis
  • medicinal chemistry
  • structure–activity relationship
  • structure-based inhibitor design
  • computational chemistry
  • NMR
  • X-ray
  • application

Published Papers (15 papers)

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Research

Jump to: Review

19 pages, 4093 KiB  
Article
Modulation of the Activity and Regioselectivity of a Glycosidase: Development of a Convenient Tool for the Synthesis of Specific Disaccharides
by Yari Cabezas-Pérusse, Franck Daligault, Vincent Ferrières, Olivier Tasseau and Sylvain Tranchimand
Molecules 2021, 26(18), 5445; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185445 - 07 Sep 2021
Viewed by 1744
Abstract
The synthesis of disaccharides, particularly those containing hexofuranoside rings, requires a large number of steps by classical chemical means. The use of glycosidases can be an alternative to limit the number of steps, as they catalyze the formation of controlled glycosidic bonds starting [...] Read more.
The synthesis of disaccharides, particularly those containing hexofuranoside rings, requires a large number of steps by classical chemical means. The use of glycosidases can be an alternative to limit the number of steps, as they catalyze the formation of controlled glycosidic bonds starting from simple and easy to access building blocks; the main drawbacks are the yields, due to the balance between the hydrolysis and transglycosylation of these enzymes, and the enzyme-dependent regioselectivity. To improve the yield of the synthesis of β-d-galactofuranosyl-(1→X)-d-mannopyranosides catalyzed by an arabinofuranosidase, in this study we developed a strategy to mutate, then screen the catalyst, followed by a tailored molecular modeling methodology to rationalize the effects of the identified mutations. Two mutants with a 2.3 to 3.8-fold increase in transglycosylation yield were obtained, and in addition their accumulated regioisomer kinetic profiles were very different from the wild-type enzyme. Those differences were studied in silico by docking and molecular dynamics, and the methodology revealed a good predictive quality in regards with the regioisomer profiles, which is in good agreement with the experimental transglycosylation kinetics. So, by engineering CtAraf51, new biocatalysts were enabled to obtain the attractive central motif from the Leishmania lipophosphoglycan core with a higher yield and regioselectivity. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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11 pages, 798 KiB  
Article
Synthesis of Tetravalent Thio- and Selenogalactoside-Presenting Galactoclusters and Their Interactions with Bacterial Lectin PA-IL from Pseudomonas aeruginosa
by Tünde Zita Illyés, Lenka Malinovská, Erzsébet Rőth, Boglárka Tóth, Bence Farkas, Marek Korsák, Michaela Wimmerová, Katalin E. Kövér and Magdolna Csávás
Molecules 2021, 26(3), 542; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26030542 - 21 Jan 2021
Cited by 2 | Viewed by 2855
Abstract
Synthesis of tetravalent thio- and selenogalactopyranoside-containing glycoclusters using azide-alkyne click strategy is presented. Prepared compounds are potential ligands of Pseudomonas aeruginosa lectin PA-IL. P. aeruginosa is an opportunistic human pathogen associated with cystic fibrosis, and PA-IL is one of its virulence factors. The [...] Read more.
Synthesis of tetravalent thio- and selenogalactopyranoside-containing glycoclusters using azide-alkyne click strategy is presented. Prepared compounds are potential ligands of Pseudomonas aeruginosa lectin PA-IL. P. aeruginosa is an opportunistic human pathogen associated with cystic fibrosis, and PA-IL is one of its virulence factors. The interactions of PA-IL and tetravalent glycoconjugates were investigated using hemagglutination inhibition assay and compared with mono- and divalent galactosides (propargyl 1-thio- and 1-seleno-β-d-galactopyranoside, digalactosyl diselenide and digalactosyl disulfide). The lectin-carbohydrate interactions were also studied by saturation transfer difference NMR technique. Both thio- and seleno-tetravalent glycoconjugates were able to inhibit PA-IL significantly better than simple d-galactose or their intermediate compounds from the synthesis. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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17 pages, 2114 KiB  
Article
Synthesis, Kinetic and Conformational Studies of 2-Substituted-5-(β-d-glucopyranosyl)-pyrimidin-4-ones as Potential Inhibitors of Glycogen Phosphorylase
by Konstantinos F. Mavreas, Dionysios D. Neofytos, Evangelia D. Chrysina, Alessandro Venturini and Thanasis Gimisis
Molecules 2020, 25(22), 5463; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25225463 - 22 Nov 2020
Cited by 2 | Viewed by 2604
Abstract
Dysregulation of glycogen phosphorylase, an enzyme involved in glucose homeostasis, may lead to a number of pathological states such as type 2 diabetes and cancer, making it an important molecular target for the development of new forms of pharmaceutical intervention. Based on our [...] Read more.
Dysregulation of glycogen phosphorylase, an enzyme involved in glucose homeostasis, may lead to a number of pathological states such as type 2 diabetes and cancer, making it an important molecular target for the development of new forms of pharmaceutical intervention. Based on our previous work on the design and synthesis of 4-arylamino-1-(β-d-glucopyranosyl)pyrimidin-2-ones, which inhibit the activity of glycogen phosphorylase by binding at its catalytic site, we report herein a general synthesis of 2-substituted-5-(β-d-glucopyranosyl)pyrimidin-4-ones, a related class of metabolically stable, C-glucosyl-based, analogues. The synthetic development consists of a metallated heterocycle, produced from 5-bromo-2-methylthiouracil, in addition to protected d-gluconolactone, followed by organosilane reduction. The methylthio handle allowed derivatization through hydrolysis, ammonolysis and arylamine substitution, and the new compounds were found to be potent (μM) inhibitors of rabbit muscle glycogen phosphorylase. The results were interpreted with the help of density functional theory calculations and conformational analysis and were compared with previous findings. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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20 pages, 3522 KiB  
Article
Synthetic Route to Glycosyl β-1C-(phosphino)-phosphonates as Unprecedented Stable Glycosyl Diphosphate Analogs and Their Preliminary Biological Evaluation
by Michaël Bosco, Su-Jin Paik, Patricia Busca, Stuart E. H. Moore and Christine Gravier-Pelletier
Molecules 2020, 25(21), 4969; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25214969 - 27 Oct 2020
Viewed by 2323
Abstract
The synthesis of glycosyl-β-1C-(phosphino)-phosphonates is a challenge since it has not yet been described. In this paper, we report an innovative synthetic method for their preparation from Glc-, Man-, and GlcNAc- lactone derivatives. The proposed original strategy involves the [...] Read more.
The synthesis of glycosyl-β-1C-(phosphino)-phosphonates is a challenge since it has not yet been described. In this paper, we report an innovative synthetic method for their preparation from Glc-, Man-, and GlcNAc- lactone derivatives. The proposed original strategy involves the addition of the corresponding δ-hexonolactones onto the dianion of (methylphosphino) phosphonate as a key step, followed by dehydration and stereoselective addition of dihydrogen on the resulting double bond. Final deprotection provides the new glycosyl diphosphate analogs in 35%, 36%, and 10% yield over 6 steps from the corresponding δ-hexonolactones. The synthetized compounds were evaluated as inhibitors of phosphatase and diphosphatase activities and found to have complex concentration-dependent activatory and inhibitory properties on alkaline phosphatase. The synthetized tools should be useful to study other enzymes such as transferases. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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23 pages, 3388 KiB  
Article
N-Alkylated Iminosugar Based Ligands: Synthesis and Inhibition of Human Lysosomal β-Glucocerebrosidase
by Andreas Wolfsgruber, Martin Thonhofer, Patrick Weber, Seyed A. Nasseri, Roland Fischer, Michael Schalli, Arnold E. Stütz, Stephen G. Withers and Tanja M. Wrodnigg
Molecules 2020, 25(20), 4618; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25204618 - 11 Oct 2020
Cited by 5 | Viewed by 3002
Abstract
The scope of a series of N-alkylated iminosugar based inhibitors in the d-gluco as well as d-xylo configuration towards their interaction with human lysosomal β-glucocerebrosidase has been evaluated. A versatile synthetic toolbox has been developed for the synthesis [...] Read more.
The scope of a series of N-alkylated iminosugar based inhibitors in the d-gluco as well as d-xylo configuration towards their interaction with human lysosomal β-glucocerebrosidase has been evaluated. A versatile synthetic toolbox has been developed for the synthesis of N-alkylated iminosugar scaffolds conjugated to a variety of terminal groups via a benzoic acid ester linker. The terminal groups such as nitrile, azide, alkyne, nonafluoro-tert-butyl and amino substituents enable follow-up chemistry as well as visualisation experiments. All compounds showed promising inhibitory properties as well as selectivities for β-glucosidases, some exhibiting activities in the low nanomolar range for β-glucocerebrosidase. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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18 pages, 2539 KiB  
Article
Synthesis of Fucose Derivatives with Thiol Motifs towards Suicide Inhibition of Helicobacter pylori
by Mark Reihill, Lorenzo Guazzelli, Han Remaut and Stefan Oscarson
Molecules 2020, 25(18), 4281; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25184281 - 18 Sep 2020
Viewed by 2904
Abstract
The syntheses of six thiol-exhibiting monosaccharides towards suicide inhibition of Helicobacter pylori are reported. Blood group Antigen Binding Adhesin (BabA), a bacterial membrane-bound lectin, binds to human ABO and Lewis b blood group structures displayed on the surface of host epithelial cells. Crystal [...] Read more.
The syntheses of six thiol-exhibiting monosaccharides towards suicide inhibition of Helicobacter pylori are reported. Blood group Antigen Binding Adhesin (BabA), a bacterial membrane-bound lectin, binds to human ABO and Lewis b blood group structures displayed on the surface of host epithelial cells. Crystal structures of the carbohydrate-recognition domain revealed a conserved disulfide bonded loop that anchors a critical fucose residue in these blood group structures. Disruption of this loop by N-acetylcysteine results in reduced BabA-mediated adherence to human gastric tissue sections and attenuated virulence in Lewis b-expressing transgenic mice. With a view of creating specific inhibitors of the lectin, we designed and successfully synthesised six fucose-derived compounds with thiol motifs to engage in a thiol-disulfide exchange with this disulfide bond of BabA and form a glycan-lectin disulfide linkage. Branching and extending the fucose backbone with 2- and 3-carbon thiol motifs delivered a range of candidates to be tested for biological activity against BabA. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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25 pages, 8035 KiB  
Article
Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine
by Patrick Weber, Martin Thonhofer, Summer Averill, Gideon J. Davies, Andres Gonzalez Santana, Philipp Müller, Seyed A. Nasseri, Wendy A. Offen, Bettina M. Pabst, Eduard Paschke, Michael Schalli, Ana Torvisco, Marion Tschernutter, Christina Tysoe, Werner Windischhofer, Stephen G. Withers, Andreas Wolfsgruber, Tanja M. Wrodnigg and Arnold E. Stütz
Molecules 2020, 25(17), 4025; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25174025 - 03 Sep 2020
Cited by 4 | Viewed by 3138
Abstract
Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the [...] Read more.
Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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10 pages, 1944 KiB  
Article
Intracellular Hydrolysis of Small-Molecule O-Linked N-Acetylglucosamine Transferase Inhibitors Differs among Cells and Is Not Required for Its Inhibition
by Elena Maria Loi, Matjaž Weiss, Stane Pajk, Martina Gobec, Tihomir Tomašič, Roland J. Pieters and Marko Anderluh
Molecules 2020, 25(15), 3381; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25153381 - 25 Jul 2020
Cited by 4 | Viewed by 3055
Abstract
O-GlcNAcylation is an essential post-translational modification that occurs on nuclear and cytoplasmic proteins, regulating their function in response to cellular stress and altered nutrient availability. O-GlcNAc transferase (OGT) is the enzyme that catalyzes this reaction and represents a potential therapeutic target, [...] Read more.
O-GlcNAcylation is an essential post-translational modification that occurs on nuclear and cytoplasmic proteins, regulating their function in response to cellular stress and altered nutrient availability. O-GlcNAc transferase (OGT) is the enzyme that catalyzes this reaction and represents a potential therapeutic target, whose biological role is still not fully understood. To support this research field, a series of cell-permeable, low-nanomolar OGT inhibitors were recently reported. In this study, we resynthesized the most potent OGT inhibitor of the library, OSMI-4, and we used it to investigate OGT inhibition in different human cell lines. The compound features an ethyl ester moiety that is supposed to be cleaved by carboxylesterases to generate its active metabolite. Our LC-HRMS analysis of the cell lysates shows that this is not always the case and that, even in the cell lines where hydrolysis does not occur, OGT activity is inhibited. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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14 pages, 4459 KiB  
Article
Synthesis of Highly Oxygenated Bicyclic Carbasugars. Remarkable Difference in the Reactivity of the d-gluco and d-xylo- Derived Trienes
by Grzegorz Witkowski, Mykhaylo A. Potopnyk, Karolina Tiara, Anna Osuch-Kwiatkowska and Sławomir Jarosz
Molecules 2020, 25(15), 3357; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25153357 - 24 Jul 2020
Cited by 4 | Viewed by 2683
Abstract
2,3,4-Tri-O-benzyl-D-xylopyranose was used as a starting material in the preparation of the corresponding triene, which underwent smooth cyclization to a polyhydroxylated hydrindane, as a single diastereoisomer. The analogous triene prepared from D-glucose did not undergo any cyclization even under high pressure. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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13 pages, 5167 KiB  
Article
Esters of Glucose-2-Phosphate: Occurrence and Chemistry
by Qiang Zhang, Si-Zhe Li, Mohammed Ahmar, Laurent Soulère and Yves Queneau
Molecules 2020, 25(12), 2829; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25122829 - 19 Jun 2020
Cited by 6 | Viewed by 2692
Abstract
Phosphodiesters of glucose-2-phosphate (G2P) are found only in few natural compounds such as agrocinopine D and agrocin 84. Agrocinopine D is a G2P phosphodiester produced by plants infected by Agrobacterium fabrum C58 and recognized by the bacterial periplasmic binding protein AccA for being [...] Read more.
Phosphodiesters of glucose-2-phosphate (G2P) are found only in few natural compounds such as agrocinopine D and agrocin 84. Agrocinopine D is a G2P phosphodiester produced by plants infected by Agrobacterium fabrum C58 and recognized by the bacterial periplasmic binding protein AccA for being transported into the bacteria before cleavage by the phosphodiesterase AccF, releasing G2P, which promotes virulence by binding the repressor protein AccR. The G2P amide agrocin 84 is a natural antibiotic produced by the non-pathogenic Agrobacterium radiobacter K84 strain used as a biocontrol agent by competing with Agrobacterium fabrum C58. G2P esters are also found in irregular glycogen structures. The rare glucopyranosyl-2-phophoryl moiety found in agrocin 84 is the key structural signature enabling its action as a natural antibiotic. Likewise, G2P and G2P esters can also dupe the Agrobacterium agrocinopine catabolism cascade. Such observations illustrate the importance of G2P esters on which we have recently focused our interest. After a brief review of the reported phosphorylation coupling methods and the choice of carbohydrate building blocks used in G2P chemistry, a flexible access to glucose-2-phosphate esters using the phosphoramidite route is proposed. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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14 pages, 2768 KiB  
Article
Enhanced Immune Response Against the Thomsen-Friedenreich Tumor Antigen Using a Bivalent Entirely Carbohydrate Conjugate
by Kristopher A. Kleski, Kevin R. Trabbic, Mengchao Shi, Jean-Paul Bourgault and Peter R. Andreana
Molecules 2020, 25(6), 1319; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25061319 - 13 Mar 2020
Cited by 10 | Viewed by 2949
Abstract
The Thomsen-Friedenreich (TF) antigen is a key target for the development of anticancer vaccines, and this ongoing challenge remains relevant due to the poor immunogenicity of the TF antigen. To overcome this challenge, we adopted a bivalent conjugate design which introduced both the [...] Read more.
The Thomsen-Friedenreich (TF) antigen is a key target for the development of anticancer vaccines, and this ongoing challenge remains relevant due to the poor immunogenicity of the TF antigen. To overcome this challenge, we adopted a bivalent conjugate design which introduced both the TF antigen and the Thomsen-nouveau (Tn) antigen onto the immunologically relevant polysaccharide A1 (PS A1). The immunological results in C57BL/6 mice revealed that the bivalent, Tn-TF-PS A1 conjugate increased the immune response towards the TF antigen as compared to the monovalent TF-PS A1. This phenomenon was first observed with enzyme-linked immunosorbent assay (ELISA) where the bivalent conjugate generated high titers of IgG antibodies where the monovalent conjugate generated an exclusive IgM response. Fluorescence-activated cell sorting (FACS) analysis also revealed increased binding events to the tumor cell lines MCF-7 and OVCAR-5, which are consistent with the enhanced tumor cell lysis observed in a complement dependent cytotoxicity (CDC) assay. The cytokine profile generated by the bivalent construct revealed increased pro-inflammatory cytokines IL-17 and IFN-γ. This increase in cytokine concentration was matched with an increase in cytokine producing cells as observed by ELISpot. We hypothesized the mechanisms for this phenomenon to involve the macrophage galactose N-acetylgalactosamine specific lectin 2 (MGL2). This hypothesis was supported by using biotinylated probes and recombinant MGL2 to measure carbohydrate-protein interactions. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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Review

Jump to: Research

25 pages, 2773 KiB  
Review
Resources and Methods for Engineering “Designer” Glycan-Binding Proteins
by Ruben Warkentin and David H. Kwan
Molecules 2021, 26(2), 380; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26020380 - 13 Jan 2021
Cited by 7 | Viewed by 4390
Abstract
This review provides information on available methods for engineering glycan-binding proteins (GBP). Glycans are involved in a variety of physiological functions and are found in all domains of life and viruses. Due to their wide range of functions, GBPs have been developed with [...] Read more.
This review provides information on available methods for engineering glycan-binding proteins (GBP). Glycans are involved in a variety of physiological functions and are found in all domains of life and viruses. Due to their wide range of functions, GBPs have been developed with diagnostic, therapeutic, and biotechnological applications. The development of GBPs has traditionally been hindered by a lack of available glycan targets and sensitive and selective protein scaffolds; however, recent advances in glycobiology have largely overcome these challenges. Here we provide information on how to approach the design of novel “designer” GBPs, starting from the protein scaffold to the mutagenesis methods, selection, and characterization of the GBPs. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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25 pages, 1708 KiB  
Review
Plant Xyloglucan Xyloglucosyl Transferases and the Cell Wall Structure: Subtle but Significant
by Barbora Stratilová, Stanislav Kozmon, Eva Stratilová and Maria Hrmova
Molecules 2020, 25(23), 5619; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25235619 - 29 Nov 2020
Cited by 31 | Viewed by 4200
Abstract
Plant xyloglucan xyloglucosyl transferases or xyloglucan endo-transglycosylases (XET; EC 2.4.1.207) catalogued in the glycoside hydrolase family 16 constitute cell wall-modifying enzymes that play a fundamental role in the cell wall expansion and re-modelling. Over the past thirty years, it has been established that [...] Read more.
Plant xyloglucan xyloglucosyl transferases or xyloglucan endo-transglycosylases (XET; EC 2.4.1.207) catalogued in the glycoside hydrolase family 16 constitute cell wall-modifying enzymes that play a fundamental role in the cell wall expansion and re-modelling. Over the past thirty years, it has been established that XET enzymes catalyse homo-transglycosylation reactions with xyloglucan (XG)-derived substrates and hetero-transglycosylation reactions with neutral and charged donor and acceptor substrates other than XG-derived. This broad specificity in XET isoforms is credited to a high degree of structural and catalytic plasticity that has evolved ubiquitously in algal, moss, fern, basic Angiosperm, monocot, and eudicot enzymes. These XET isoforms constitute gene families that are differentially expressed in tissues in time- and space-dependent manners during plant growth and development, and in response to biotic and abiotic stresses. Here, we discuss the current state of knowledge of broad specific plant XET enzymes and how their inherently carbohydrate-based transglycosylation reactions tightly link with structural diversity that underlies the complexity of plant cell walls and their mechanics. Based on this knowledge, we conclude that multi- or poly-specific XET enzymes are widespread in plants to allow for modifications of the cell wall structure in muro, a feature that implements the multifaceted roles in plant cells. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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19 pages, 6925 KiB  
Review
The Glycan Structure of T. cruzi mucins Depends on the Host. Insights on the Chameleonic Galactose
by María Eugenia Giorgi and Rosa M. de Lederkremer
Molecules 2020, 25(17), 3913; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25173913 - 27 Aug 2020
Cited by 13 | Viewed by 5865
Abstract
Trypanosoma cruzi, the protozoa that causes Chagas disease in humans, is transmitted by insects from the Reduviidae family. The parasite has developed the ability to change the structure of the surface molecules, depending on the host. Among them, the mucins are the [...] Read more.
Trypanosoma cruzi, the protozoa that causes Chagas disease in humans, is transmitted by insects from the Reduviidae family. The parasite has developed the ability to change the structure of the surface molecules, depending on the host. Among them, the mucins are the most abundant glycoproteins. Structural studies have focused on the epimastigotes and metacyclic trypomastigotes that colonize the insect, and on the mammal trypomastigotes. The carbohydrate in the mucins fulfills crucial functions, the most important of which being the accepting of sialic acid from the host, a process catalyzed by the unique parasite trans-sialidase. The sialylation of the parasite influences the immune response on infection. The O-linked sugars have characteristics that differentiate them from human mucins. One of them is the linkage to the polypeptide chain by the hexosamine, GlcNAc, instead of GalNAc. The main monosaccharide in the mucins oligosaccharides is galactose, and this may be present in three configurations. Whereas β-d-galactopyranose (β-Galp) was found in the insect and the human stages of Trypanosoma cruzi, β-d-galactofuranose (β-Galf) is present only in the mucins of some strains of epimastigotes and α-d-galactopyranose (α-Galp) characterizes the mucins of the bloodstream trypomastigotes. The two last configurations confer high antigenic properties. In this review we discuss the different structures found and we pose the questions that still need investigation on the exchange of the configurations of galactose. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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64 pages, 5893 KiB  
Review
Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review
by Igor Tvaroška, Chandrabose Selvaraj and Jaroslav Koča
Molecules 2020, 25(12), 2835; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25122835 - 19 Jun 2020
Cited by 39 | Viewed by 10524
Abstract
Selectins belong to a group of adhesion molecules that fulfill an essential role in immune and inflammatory responses and tissue healing. Selectins are glycoproteins that decode the information carried by glycan structures, and non-covalent interactions of selectins with these glycan structures mediate biological [...] Read more.
Selectins belong to a group of adhesion molecules that fulfill an essential role in immune and inflammatory responses and tissue healing. Selectins are glycoproteins that decode the information carried by glycan structures, and non-covalent interactions of selectins with these glycan structures mediate biological processes. The sialylated and fucosylated tetrasaccharide sLex is an essential glycan recognized by selectins. Several glycosyltransferases are responsible for the biosynthesis of the sLex tetrasaccharide. Selectins are involved in a sequence of interactions of circulated leukocytes with endothelial cells in the blood called the adhesion cascade. Recently, it has become evident that cancer cells utilize a similar adhesion cascade to promote metastases. However, like Dr. Jekyll and Mr. Hyde’s two faces, selectins also contribute to tissue destruction during some infections and inflammatory diseases. The most prominent function of selectins is associated with the initial stage of the leukocyte adhesion cascade, in which selectin binding enables tethering and rolling. The first adhesive event occurs through specific non-covalent interactions between selectins and their ligands, with glycans functioning as an interface between leukocytes or cancer cells and the endothelium. Targeting these interactions remains a principal strategy aimed at developing new therapies for the treatment of immune and inflammatory disorders and cancer. In this review, we will survey the significant contributions to and the current status of the understanding of the structure of selectins and the role of selectins in various biological processes. The potential of selectins and their ligands as therapeutic targets in chronic and acute inflammatory diseases and cancer will also be discussed. We will emphasize the structural characteristic of selectins and the catalytic mechanisms of glycosyltransferases involved in the biosynthesis of glycan recognition determinants. Furthermore, recent achievements in the synthesis of selectin inhibitors will be reviewed with a focus on the various strategies used for the development of glycosyltransferase inhibitors, including substrate analog inhibitors and transition state analog inhibitors, which are based on knowledge of the catalytic mechanism. Full article
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
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